CS235170B1 - Process for preparing 5-methyl-2-mercapto-1,3,4-thiadiazole - Google Patents

Abstract

The invention relates to a method of preparing 5-methyl-2-mer!captol-1,3,4-thiadiazole of the formula I CH SH (I) The compound of the formula I is used as an intermediate for semi-synthetic cephalosporins. According to the invention, the compound of formula I is prepared by reacting carbon disulfide acetylhydrazine and an organic or inorganic base and subsequent dehydration with acidic agents.

Description

3 4 235170

This invention relates to a process for the preparation of 5-methyl-2-mercapto-1,3,4-thiadiazole of formula (I). This compound is used as an intermediate in the preparation of highly potent cephalosporins.

The compounds of formula I have so far been prepared by two-stage synthesis from 2-amino-5-methyl-1,3,4-thiadiazole by diazotization to give 2-bromo-5-methyl-1,3,4-thiadiazole, which reacts with thiourea in the presence of a suitable base to provide the desired compound [Sondstrom, Acta Chim. Scand. 20, 57 (1966)]. Another known method of preparing a compound of formula I is by condensing acetiminoalkyl ether hydrochloride with a picolinium dithiocarbazide in an isopropanol medium (Jag 2, Pat. No. 72,32071). The last known method for the preparation of compound I is condensation ofioacetamide, hydrazine, carbon disulphide in the presence of an organic or inorganic base in an ethanol medium (Eli Lilly Co., U.S.A.O168 044).

The preparation of compound I according to the invention is based on the reaction of acetylhydrazine with sulfur-carbon and alkali hydroxide, preferably sodium hydroxide, optionally potassium hydroxide, or organic bases, for example piperidine, pyridine, its alkyl derivatives, trisubstituted amines, the substituents of which may be alkyl, cycloalkyl, optionally aryls having a carbon number of 3 to 15 in the aqueous medium to give the corresponding soliacetyldithiocarbamic acid of the general formula II

CH 3 -CO-NHNH-CS 2 M (Π) wherein M represents an alkali metal cation, or pyridinium, allkylpyridinium, optionally trisubstituted with ammonium, in which the substituents may be alkyl, cycloalkyl, optionally aryls having carbon numbers of 3 to 15, without further purification, the reaction is carried out with the dehydrating agent on compound I. Phosphoric acid, polyphosphoric acid, preferably sulfuric acid, is used as the dehydrating agent.

The process of the invention is carried out by adding to the aqueous solution 1 mol. acetyl hydrazine and 0.8 to 1.3 moles. 0.8 to 1.3 moles of a part of the alkaline hydroxide dissolved in water or one of the above organic bases is added. of carbon disulphide. Any carbon disulfide is a very toxic and highly volatile compound with a low flash point, and is added to the liquid mixture at temperatures of 9 to 30 ° C, preferably below 7 ° C. C. In such a temperature-sensitive mode and in the water environment, the risk associated with the use of larger amounts of carbon disulphide in operation is substantially reduced. After the carbon disulfide has been added to the reaction mixture, it is allowed to self-warm the room temperature and the reaction is completed by stirring at this temperature. The resulting salt of formula (II) is precipitated from the real environment by the addition of a suitable organic solvent, for example dioxane, isopropanol, tetrahydrofuran, acetone, with the exception of ethanol, by pouring the reaction mixture into one of the two. of said solvents, preferably by pouring the solvent into the reaction mixture. The precipitated salt of Formula II is isolated by filtration on a suction, pressure filter, or centrifuged. After drying in a hot-air or vacuum dryer, it is used without further purification in the dehydrogenation reaction. This is carried out according to the invention in such a way that the crude salt of the general formula II is introduced into the dehydrating agent with stirring at temperatures of 0 to 60 ° C, preferably at 2 to 15 ° C. As the dehydrating agent, phosphoric acid, polyphosphoric acid, preferably acidic sulfuric acid, may be used. Upon introduction of the salt of formula (II) into the dehydrating agent, it is quenched by spontaneous heating to room temperature and stirred at this temperature. The cyclization product is isolated by pouring the reaction mixture onto ice and the insoluble compound of formula I is isolated by filtration or centrifugation. The crude compound I obtained is purified by crystallization from a suitable solvent. The main advantage of the process according to the invention is the achievement of higher yields of 5 to 7% compared to known processes. A further advantage is the better quality of the compound of formula I (expressed as its color), due to the reaction in water. A further advantage of the process according to the invention is that instead of being used in organic flammable solvents, water is used, which reduces the risk of using carbon disulphide.

The process of the invention is illustrated by the following non-limiting examples. EXAMPLE 1 A solution of 6.4 g of potassium hydroxide in 5.7 ml of water is added to 7.19 g of acetylhydrazine. The resulting solution is left at 5 DEG C. and 4.2 ml of carbon disulphide are added at such a rate that the temperature not exceed 7 ° C. The reaction is completed by stirring at room temperature for 1 hour. The reaction mixture is poured into 75 ml of ethanol. The suspension ® was stirred for 1 hour at room temperature and cooled to 10 ° C. The precipitate was filtered off and washed with ether to give 18.2 g (100%) of potassium acetyldithiocarbate, which was added to 50 ml of 96% sulfuric acid so that the temperature did not exceed 5 ° C. After stirring for 1 hour at room temperature, the reaction mixture was poured onto ice. The product is filtered off, washed with water and dried.

Claims (3)

Recrystallization from methanol gave 11.1 g of 5-methyl-2-mercapto-1,3,4-thiadiazole (80%). mp 183-184 ° C. EXAMPLE 2 To a mixture of 4.03 g of acetylhydrazine, 4.6 g of pyridine and 2 ml of water was added at 5 DEG C. 2.3 ml of carbon disulfide. The reaction is completed by stirring the reaction mixture for 20 minutes at room temperature. The reaction mixture is poured into 30 ml of acetone and the treated pyridinium N-acetyldi-thiocarbazate is filtered off and dried. The resultant is successively introduced into 15 ml of concentrated sulfuric acid at 5 ° C. Quench the reaction for 10 minutes at 20 ° C. The mixture is poured onto ice and the treated crystals are filtered and washed with water. 6.2 g of 5-methyl-2-mercapto-1,3,4-thiadiazole are obtained. Mp 180-182 ° C. EXAMPLE 3 To a solution of 13.7 g of acetylhydrazine and 7.4 g of sodium hydroxide in 11 ml of water was added 7.9 ml of carbon disulfide at 5 ° C. After stirring at room temperature for 1 hour, the reaction mixture is brought to crystallization by the addition of 600 ml of isopropyl alcohol. The precipitated material is filtered off and subsequently cyclized according to Example 1. B: 21.2 g of 5-methyl-2-mercapto-1,3,4-thiadiazole are obtained. Mp 178-180 CC. Example 4 A mixture of 2.9 g of acetylhydrazine, 1.70 ml of sulfur-carbon and 5.0 g of lutidine in 3 ml of water was stirred at 7 ° C for 1 hour. The resulting solution was crystallized by the addition of 35 ml of tetrahydrofuran. The sapo drying material is added to a mixture of 20 ml of ortho-phosphoric acid and 15 g of phosphorus pentoxide at 5 ° C. The reaction mixture was stirred at 160 ° C for 4 hours. The thick solution is poured into 1 liter of water and neutralized by the addition of sodium bicarbonate. The precipitated solid is filtered off and washed with water. Crystallization from methanol gave 4.4 g of 5-methyl-2-mercapto-1,3,4-thiadiazole. Mp 181-182 ° C. EXAMPLE 5 To a solution of 5.8 g of acetylhydrazine, 10 ml of triethylamine and 10 ml of water was added 3.5 ml of diatomaceous earth at 5 ° C. The reaction is completed by stirring the reaction mixture for 30 minutes at the indicated temperature. Addition of 400 ml of isopropanol gives a solid which, by cyclization according to Example 1, gives 7.8 g of 5-methyl-2-mercapto-1,3,4-thiadiazole. Mp 178-180 ° C. OBJECT 1. A process for the preparation of 5-methyl-2-mercapto-1,3,4-thiadiazole of formula (I), characterized in that it is reacted with 1 mol. parts of acetylhydrazine with 0.8 to 1.3 moles of carbon disulfide and 0.8 to 1.3 moles. dielomalkalic hydroxide, preferably potassium, optionally sodium, or piperidine, pyridine, optionally its alkyl derivatives, or substituted-amines, in which the substituents may be alkyl, cycloalkyl, optionally aryls having a carbon number of 3 to T 5 in the aqueous medium at wherein the corresponding acetyldithiocarbamic acid salt of formula (II) is selected from CH 2 CO-NHNH-CS 2 M (II) wherein M is an alkali metal or pyridinium cation, optionally an alkylpyridinium or trisubstituted ammonium, in which the substituents may be alkyl, cycloalkyl, optionally aryl. with a carbon number of 3 to 15, and this is subjected to a cyclization reaction with a dehydrating agent at a temperature of 0 to 60 ° C, preferably at 2 to 15 ° C. 2. A process according to claim 1, wherein the salt of acetyldithiocarbamic acid of formula (II) is isolated from the reaction mixture by precipitation with an organic solvent such as dioxane, isopropanol, tetrahydrofuran, acetone or ethanol. 3. The process according to claim 1, wherein the dehydrating agent used in the cyclization reaction is phosphoric acid, polyphosphoric acid, preferably sulfuric acid.